Macrophage migration inhibitory factor facilitates the therapeutic efficacy of mesenchymal stem cells derived exosomes in acute myocardial infarction through upregulating miR-133a-3p

Zhu, Wenwu; Sun, Ling; Zhao, Pengcheng; Liu, Yaowu; Zhang, Jian; Zhang, Yuelin; Hong, Yan; Zhu, Yeqian; Lu, Yao; Zhao, Wei; Chen, Xinguang; Zhang, Fengxiang

doi:10.1186/s12951-021-00808-5

Cited by 87 publications

(75 citation statements)

References 45 publications

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“…Therefore, modifying MSC-EXO in vitro to alter their molecular components is a novel strategy to augment their cardioprotective effects. EXO derived from MSCs overexpressing macrophage migration inhibitory factor were superior to MSC-EXO in improving heart function following infarction in rats [ 38 ]. In addition to genetic modification, environmental stimuli are another novel strategy to optimize MSC-EXO.…”

Section: Discussionmentioning

confidence: 99%

Hemin enhances the cardioprotective effects of mesenchymal stem cell-derived exosomes against infarction via amelioration of cardiomyocyte senescence

et al. 2021

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Background Application of mesenchymal stem cell-derived exosomes (MSC-EXO) has emerged as a novel therapeutic strategy for myocardial infarction (MI). Our previous study showed that pretreatment with hemin, a potent heme oxygenase-1 (HO-1) inducer, enhanced the cardioprotective effects of MSCs in a mouse model of MI. This study aimed to investigate the therapeutic effects of EXO derived from hemin-pretreated MSCs (Hemin-MSC-EXO) in MI and explore the potential mechanisms. Methods MSC-EXO and Hemin-MSC-EXO were collected and characterized. MSC-EXO and Hemin-MSC-EXO were intramuscularly injected into the peri-infarct region in a mouse model of MI. Heart function of mice was assessed by echocardiography. The mitochondrial morphology of neonatal mice cardiomyocytes (NMCMs) under serum deprivation and hypoxic (SD/H) conditions was examined by Mitotracker staining. The cellular senescence of NMCMs was determined by senescence-associated-β-galactosidase assay. A loss-of-function approach was adopted to determine the role of Hemin-MSC-exosomal-miR-183-5p in the regulation of cardiomyocyte senescence Results EXO were successfully isolated from the supernatant of MSCs and Hemin-pretreated MSCs. Compared with MSC-EXO, injection of Hemin-MSC-EXO significantly improved cardiac function and reduced fibrosis. Both MSC-EXO and Hemin-MSC-EXO ameliorated cardiomyocyte senescence and mitochondrial fission in vitro and in vivo, and the latter exhibited better protective effects. MicroRNA sequencing revealed a higher level of miR-183-5p in Hemin-MSC-EXO than in MSC-EXO. MiR-183-5p knockdown partially abrogated the protective effects of Hemin-MSC-EXO in attenuating mitochondrial fission and cellular senescence of cardiomyocytes induced by SD/H. High mobility group box-1 (HMGB1) abundance was lower in Hemin-MSC-EXO-treated than MSC-EXO-treated mouse hearts, and HMGB1 was identified as one of the potential target genes of miR-183-5p. Mechanistically, Hemin-MSC-EXO inhibited SD/H-induced cardiomyocyte senescence partially by delivering miR-183-5p into recipient cardiomyocytes via regulation of the HMGB1/ERK pathway. Furthermore, knockdown of miR-183-5p reduced the Hemin-MSC-EXO-mediated cardioprotective effects in a mouse model of MI. Conclusion Our results reveal that Hemin-MSC-EXO are superior to MSC-EXO in treating MI. Exosomal miR-183-5p mediates, at least partially, the cardioprotective effects of Hemin-MSC-EXO by inhibiting cardiomyocyte senescence via regulation of the HMGB1/ERK pathway. This study highlights that MSC-EXO have high translational value in repairing cardiac dysfunction following infarction. Graphic abstract

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Section: Discussionmentioning

confidence: 99%

Hemin enhances the cardioprotective effects of mesenchymal stem cell-derived exosomes against infarction via amelioration of cardiomyocyte senescence

et al. 2021

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“…It has been reported that MIF plays important roles in macrophage behaviors and bone healing ( Liu et al, 2021 ; Zhu et al, 2021 ). Figure 2D showed that MIF deposited in hucMSC-ECM was rich in content.…”

Section: Resultsmentioning

confidence: 99%

Macrophage-Mediated Bone Formation in Scaffolds Modified With MSC-Derived Extracellular Matrix Is Dependent on the Migration Inhibitory Factor Signaling Pathway

Deng

Tan

Dai

et al. 2021

Front. Cell Dev. Biol.

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The positive role of macrophages in the osteogenesis of mesenchymal stem cells (MSCs) has been a recent research focus. On the other hand, MSCs could carefully regulate the paracrine molecules derived from macrophages. Human umbilical cord mesenchymal stem cells (hucMSCs) can reduce the secretion of inflammatory factors from macrophages to improve injury healing. hucMSC-derived extracellular matrix (hucMSC-ECM) has the similar effect to hucMSCs, which could combat the inflammatory response of macrophages. Additionally, MSC-derived extracellular matrix also enhanced bone regeneration by inhibiting osteoclastic differentiation of monocyte/macrophage lineage. However, whether hucMSC-ECM could improve bone formation by guiding macrophage-induced osteogenic differentiation of MSCs is unknown. Here, we present decalcified bone scaffolds modified by hucMSC-derived extracellular matrix (DBM-ECM), which maintained multiple soluble cytokines from hucMSCs, including macrophage migration inhibitory factor (MIF). Compared with DBM, the DBM-ECM scaffolds induced bone formation in an improved heterotopic ossification model of severe combined immunodeficiency (SCID) mice in a macrophage-dependent manner. Macrophages cocultured with DBM-ECM expressed four osteoinductive cytokines (BMP2, FGF2, TGFβ3 and OSM), which were screened out by RNA sequencing and measured by qPCR and western blot. The conditioned medium from macrophages cocultured with DBM-ECM improved the osteogenic differentiation of hBMSCs. Furthermore, DBM-ECM activated CD74/CD44 (the typical MIF receptors) signal transduction in macrophages, including phosphorylation of P38 and dephosphorylation of c-jun. On the other side, the inhibitory effects of the DBM-ECM scaffolds with a deficient of MIF on osteogenesis in vitro and in vivo revealed that macrophage-mediated osteogenesis depended on MIF/CD74 signal transduction. The results of this study indicate that the coordinated crosstalk of macrophages and MSCs plays a key role on bone regeneration, with an emphasis on hucMSC-ECM constructing a macrophage-derived osteoinductive microenvironment.

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“…The total cellular and exosomal RNA was extracted using Trizol reagent (Life Technologies, USA) according to the manufacturer's instructions. 14 A stem-loop-speci c primer method was used to measure miR-21-5p expression, as described previously. 20 The sequences of primers used in the study were shown in Table S1.…”

Section: Quantitative Real-time Pcr (Qrt-pcr)mentioning

confidence: 99%

“…Protein extraction and Western blot (WB) analysis were performed as previously stated. 14 Brie y, cells were washed with PBS and lysed with lysis buffer on ice for 20 minutes. The total cell protein concentration was detected by the BCA Protein Assay Kit.…”

Section: Western Blotmentioning

confidence: 99%

“…Eight-week-old male Sprague-Dawley (SD) rats obtained from the experimental animal center of Nanjing Medical University were randomly divided into 4 groups: sham operation group (Sham group, n=6), PBS injection group (PBS group, n=6), Ctrl-Exo injection group (Ctrl-Exo group, n=6), and IFN-γ-Exo injection group (IFN-γ-Exo group, n=6). Brie y, as previously described 14 , left anterior descending artery (LAD) was ligated, and Exos (50µL, 1µg/µL) or PBS was injected around the infarct area in rats. All surgeries and subsequent analyses were blinded for intervention.…”

Section: Model Histological Analysis and Immuno Uorescence Stainingmentioning

confidence: 99%

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IFN-γ Enhances the Efficacy of Exosomes Derived from Mesenchymal Stem Cells in Myocardial Infarction Rats via miR-21 Stimulated by STAT1

Zhang

Mao

et al. 2021

Preprint

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Background: Mesenchymal stem cells (MSCs) activated with IFN-γ elicit more powerful physical effects. Exosomes (Exos) secreted from MSCs have protective against myocardial injury. The aim of this study was to investigate whether Exsos derived from IFN-γ-pretreated MSCs exhibit more potent cardioprotective function and the underlying mechanisms. Methods: Exos were isolated from MSCs (Ctrl-Exo) and IFN-γ-primed MSCs (IFN-γ-Exo) and were then delivered to H9c2 cells or human umbilical vein endothelial cells (HUVECs) in vitro under oxygen and glucose deprivation (OGD) condition or in vivo in an infarcted rat heart. RNA sequencing was to identify the different expressed functional transcription factor (TF). Quantitative reverse transcription-PCR (qPCR) was to confirm the upregulated TF and miRNA in IFN-γ-primed MSCs. Dual-luciferase reporter gene assay were to analyze the transcriptional regulation of miRNAs by STAT1. The target of miR-21-5p (miR-21) was disclosed by luciferase reporter assays and qPCR. The function of BTG2 was verified in vitro under OGD condition.Result: IFN-γ-Exo accelerated migration, tube-like structure formation, and prevented H9c2 from OGD-induced apoptosis. Similarly, IFN-γ-Exo leaded to further reduction in fibrosis size, reduced cardiomyocyte apoptosis and improved cardiac function compared to Ctrl-Exo. miR-21 was significantly upregulated in both IFN-γ-primed MSCs and IFN-γ-Exo. STAT1 transcriptionally induced miR-21 expression. Up-regulated miR-21 can inhibit the expression of BTG2. BTG2 promoted H9c2 cells apoptosis and reversed the protective effect of miR-21 under OGD environment.Conclusion: IFN-γ-Exo have enhanced therapeutic efficacy against acute MI possibly through promoting angiogenesis and anti-apoptotic effect through increasing the level of miR-21, which directly targeted on BTG2.

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Macrophage migration inhibitory factor facilitates the therapeutic efficacy of mesenchymal stem cells derived exosomes in acute myocardial infarction through upregulating miR-133a-3p

Cited by 87 publications

References 45 publications

Hemin enhances the cardioprotective effects of mesenchymal stem cell-derived exosomes against infarction via amelioration of cardiomyocyte senescence

Hemin enhances the cardioprotective effects of mesenchymal stem cell-derived exosomes against infarction via amelioration of cardiomyocyte senescence

Macrophage-Mediated Bone Formation in Scaffolds Modified With MSC-Derived Extracellular Matrix Is Dependent on the Migration Inhibitory Factor Signaling Pathway

IFN-γ Enhances the Efficacy of Exosomes Derived from Mesenchymal Stem Cells in Myocardial Infarction Rats via miR-21 Stimulated by STAT1

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